BARC (BMP Antagonist Regulated in Cancer) is a novel BMP (bone morphogenic protein) antagonist we recently discovered as part of a search for secretory genes altered in cancer. BARC is strikingly downregulated in kidney cancers [in 19/20 human tissues tested], has sequence similarity to a superfamily of growth regulatory proteins, and contains a perfect sequence match for a cystine knot motif that functions in proteins known to bind and inactivate BMPs. Further, our preliminary data show that overexpression of BARC substantially inhibits kidney cancer cell growth. This preliminary evidence points to the involvement of BARC in growth regulation of the kidney, and suggests that BARC dysfunction may be associated with kidney cancer. The hypothesis to be tested in this proposal is that BARC functions as a physiologic growth antagonist in the normal kidney, and that its down-regulation induces proliferation in kidney epithelium, an important prerequisite for renal oncogenesis. Our Specific Aims are to (1) Test the role of BARC in growth regulation of normal kidney and kidney cancer using conditional expression, recombinant protein, and shRNA; (2) Identify growth-regulatory signal transduction pathways inhibited by BARC using SMAD reporter assays and immunoblots for activated SMAD; (3) Assess expression of BARC in normal and malignant kidney tissue using immunonhistochemistry. Although much remains to be accomplished, our preliminary observations thus far suggests that BARC may be a novel tumor suppressor gene - a gene whose normal function is to suppress proliferation in the normal kidney, and whose absence is permissive for kidney cancer development. The experiments in this proposal will test this hypothesis, and lay the groundwork for the potential use of BARC in kidney cancer prognosis and therapy.